HFA Suspension Formulations Containing An Anticholinergic

ABSTRACT

The invention relates to propellant gas formulations containing suspensions of the crystalline monohydrate of (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl -3-oxa-9-azoniatricyclo[3.3.1.0 2,4 ]nonane-bromide.

APPLICATION DATA

This application claims benefit to German application no. DE 102 14263.7 filed Mar. 28, 2002 and U.S. provisional application No.60/386,145 filed Jun. 5, 2002.

FIELD OF THE INVENTION

The invention relates to pressurised gas preparations for metered-doseaerosols with suspension formulations of the crystalline monohydrate of(1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonane-bromide,processes for the preparation thereof and the use thereof for preparinga pharmaceutical composition, particularly for preparing apharmaceutical composition with an anticholinergic activity.

BACKGROUND TO THE INVENTION

The compound(1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonane-bromide,is known from European Patent Application EP 418 716A1 and has thefollowing chemical structure:

The compound has valuable pharmacological properties and is known by thename tiotropium bromide (BA679). Tiotropium bromide is a highlyeffective anticholinergic and can therefore provide therapeutic benefitin the treatment of asthma or COPD (chronic obstructive pulmonarydisease).

Tiotropium bromide is preferably administered by inhalation.

The aim of the present invention is to prepare HFA-metered-dose aerosolscontaining tiotropium bromide as the sole active ingredient in suspendedform.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that, depending on the choice of conditions which canbe used when purifying the crude product obtained after industrialmanufacture, tiotropium bromide occurs in various crystallinemodifications.

It has been found that these different modifications can be deliberatelyproduced by selecting the solvents used for the crystallisation as wellas by a suitable choice of the process conditions used in thecrystallisation process. For the purposes of preparing the formulationsaccording to the invention, crystalline tiotropium bromide monohydratehas proved particularly suitable.

Accordingly, the present invention relates to suspensions of crystallinetiotropium bromide monohydrate in the propellant gases HFA 227 and/orHFA 134a, optionally in admixture with one or more other propellantgases, preferably selected from the group consisting of propane, butane,pentane, dimethylether, CHClF₂, CH₂F₂, CF₃CH₃, isobutane, isopentane andneopentane.

Preferred suspensions according to the invention are those which containas propellant gas HFA 227 on its own, a mixture of HFA 227 and HFA 134aor HFA 134a on its own. If a mixture of propellant gases HFA 227 and HFA134a is used in the suspension formulations according to the invention,the weight ratios in which these two propellant gas components are usedmay be freely selected. If in the suspension formulations according tothe invention one or more other propellant gases are used in addition tothe propellant gases HFA 227 and/or HFA 134a , selected from the groupconsisting of propane, butane, pentane, dimethylether, CHClF₂, CH₂F₂,CF₃CH₃, isobutane, isopentane and neopentane, the proportion of thisother propellant gas component is preferably less than 50%, preferablyless than 40%, more preferably less than 30%.

The suspensions according to the invention preferably contain between0.001 and 0.8% tiotropium. Suspensions which contain 0.08 to 0.5%, morepreferably 0.2 to 0.4% tiotropium are preferred according to theinvention.

By tiotropium is meant the free ammonium cation. The propellant gassuspensions according to the invention are characterised in that theycontain tiotropium in the form of the crystalline tiotropium bromidemonohydrate which is exceptionally suitable for this application.Accordingly, the present invention preferably relates to suspensionswhich contain between 0.0012 and 1% crystalline tiotropium bromidemonohydrate.

Of particular interest according to the invention are suspensions whichcontain 0.1 to 0.62%, more preferably 0.25 to 0.5% crystallinetiotropium bromide monohydrate.

The percentages specified within the scope of the present invention arealways percent by mass. If parts by mass of tiotropium are given inpercent by mass, the corresponding values for the crystalline tiotropiumbromide monohydrate which is preferably used within the scope of thepresent invention may be obtained by multiplying by a conversion factorof 1.2495.

In some cases within the scope of the present invention the termsuspension formulation may be used instead of the term suspension. Thetwo terms are to be regarded as interchangeable within the scope of thepresent invention.

The propellant-containing inhalation aerosols or suspension formulationsaccording to the invention may also contain other ingredients such assurface-active agents (surfactants), adjuvants, antioxidants orflavourings.

The surface-active agents (surfactants) which may be contained in thesuspensions according to the invention are preferably selected fromamong Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08,isopropylmyristate, oleic acid, propyleneglycol, polyethyleneglycol,Brij, ethyloleate, glyceryl trioleate, glyceryl monolaurate, glycerylmonooleate, glyceryl monosterate, glyceryl monoricinoleate,cetylalcohol, sterylalcohol, cetylpyridinium chloride, block polymers,natural oil, ethanol and isopropanol. Of the abovementioned suspensionadjuvants Polysorbate 20, Polysorbate 80, Myvacet 9-45, Myvacet 9-08 orisopropylmyristate are preferably used. Myvacet 9-45 orisopropylmyristate are particularly preferred. Where the suspensionsaccording to the invention contain surfactants, these are preferablypresent in an amount of 0.0005-1%, more preferably 0.005-0.5%.

The adjuvants optionally contained in the suspensions according to theinvention are preferably selected from among alanine, albumin, ascorbicacid, aspartame, betaine, cysteine, phosphoric acid, nitric acid,hydrochloric acid, sulphuric acid and citric acid. Of these, ascorbicacid, phosphoric acid, hydrochloric acid or citric acid are preferred,while hydrochloric acid or citric acid is more preferable.

Where the suspensions according to the invention contain adjuvants,these are preferably present in an amount of 0.0001-1.0%, preferably0.0005-0.1%, more preferably 0.001-0.01%, while an amount of from0.001-0.005% is particularly preferred according to the invention.

The antioxidants optionally contained in the suspensions according tothe invention are preferably selected from among ascorbic acid, citricacid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene,butylhydroxyanisol and ascorbyl palmitate, of which tocopherols,butylhydroxytoluene, butylhydroxyanisol and ascorbyl palmitate arepreferred.

The flavourings which may be contained in the suspensions according tothe invention are preferably selected from among peppermint, saccharine,Dentomint®, aspartame and ethereal oils (e.g. cinnamon, aniseed,menthol, camphor), of which peppermint or Dentomint® is particularlypreferred.

For administration by inhalation it is necessary to prepare the activesubstance in finely divided form. The crystalline tiotropium bromidemonohydrate which may be obtained as detailed in the experimentalsection is either ground (micronised or obtained in finely divided formby other technical methods known in principle in the art (such asprecipitation and spray drying). Methods of micronising activesubstances are known in the art. Preferably, after micronisation, theactive substance has an average particle size of 0.5 to 10 μm,preferably 1 to 6 μm, more preferably 1.5 to 5 μm. Preferably, at least50%, more preferably at least 60%, most preferably at least 70% of theparticles of active substance have a particle size which is within theranges specified above. More preferably, at least 80%, most preferablyat least 90% of the particles of active substance have a particle sizewithin the ranges specified above.

Surprisingly, it has been found that it is also possible to preparesuspensions which contain, apart from the abovementioned propellantgases, only the active substance and no other additives. Accordingly, inanother aspect, the present invention relates to suspensions whichcontain only the active substance and no other additives.

The suspensions according to the invention may be prepared by methodsknown in the art. For this the ingredients of the formulation are mixedwith the propellant gas or gases (optionally at low temperatures) andtransferred into suitable containers.

The propellant gas-containing suspensions according to the inventionmentioned above may be administered using inhalers known in the art(pMDIs=pressurised metered dose inhalers). Accordingly, in anotheraspect, the present invention relates to pharmaceutical compositions inthe form of suspensions as hereinbefore described combined with one ormore inhalers suitable for administering these suspensions. In addition,the present invention relates to inhalers which are characterised inthat they contain the propellant gas-containing suspensions describedabove according to the invention. The present invention also relates tocontainers (e.g. cartridges) which are fitted with a suitable valve andcan be used in a suitable inhaler and which contain one of theabove-mentioned propellant gas-containing suspensions according to theinvention. Suitable containers (e.g. cartridges) and methods of fillingthese cartridges with the propellant gas-containing suspensionsaccording to the invention are known from the prior art.

In view of the pharmaceutical activity of tiotropium the presentinvention further relates to the use of the suspensions according to theinvention for preparing a drug for administration by inhalation or bynasal route, preferably for preparing a drug for the treatment byinhalation or by nasal route of diseases in which anticholinergics mayprovide a therapeutic benefit.

Most preferably, the invention further relates to the use of thesuspensions according to the invention for preparing a pharmaceuticalcomposition for the treatment by inhalation of respiratory complaints,preferably asthma or COPD.

The Examples that follow serve to illustrate the present invention morefully by way of example, without restricting it to their content.

Starting Materials

Crystalline Tiotropium Bromide Monohydrate:

The tiotropium obtained according to EP 418 716 A1 may be used toprepare the crystalline tiotropium bromide monohydrate. This is thenreacted as described below. 15.0 kg of tiotropium bromide are added to25.7 kg of water in a suitable reaction vessel. The mixture is heated to80-90° C. and stirred at constant temperature until a clear solution isformed. Activated charcoal (0.8 kg), moistened with water, is suspendedin 4.4 kg of water, this mixture is added to the solution containingtiotropium bromide and rinsed with 4.3 kg of water. The mixture thusobtained is stirred for at least 15 min. at 80-90° C. and then filteredthrough a heated filter into an apparatus which has been preheated to anouter temperature of 70° C. The filter is rinsed with 8.6 kg of water.The contents of the apparatus are cooled to a temperature of 20-25° C.at a rate of 3-5° C. every 20 minutes. Using cold water the apparatus iscooled further to 10-15° C. and crystallisation is completed by stirringfor at least another hour. The crystals are isolated using a suctionfilter drier, the crystal slurry isolated is washed with 9 L of coldwater (10-15° C.) and cold acetone (10-15° C.). The crystals obtainedare dried at 25° C. for 2 hours in a nitrogen current. Yield: 13.4 kg oftiotropium bromide monohydrate (86% of theory). The tiotropium bromidemonohydrate obtainable using the method described above was investigatedby DSC (Differential Scanning Calorimetry). The DSC diagram shows twocharacteristic signals. The first, relatively broad, endothermic signalbetween 50-120° C. can be attributed to the dehydration of thetiotropium bromide monohydrate into the anhydrous form. The second,relatively sharp, endothermic peak at 230±5° C. can be put down to themelting of the substance. This data was obtained using a Mettler DSC 821and evaluated using the Mettler STAR software package. The data wasrecorded at a heating rate of 10 K/min.

The crystalline tiotropium bromide monohydrate was characterised by IRspectroscopy. The data was obtained using a Nicolet FTIR spectrometerand evaluated with the Nicolet OMNIC software package, version 3.1. Themeasurement was carried out with 2.5 μmol of tiotropium bromidemonohydrate in 300 mg of KBr. The following Table shows some of theessential bands of the IR spectrum. Wave number (cm⁻¹) Attribution Typeof oscillation 3570, 3410 O—H elongated oscillation 3105 Aryl C—Helongated oscillation 1730 C═O elongated oscillation 1260 Epoxide C—Oelongated oscillation 1035 Ester C—OC elongated oscillation  720Thiophene cyclic oscillation

The monocrystal X-ray structural analysis carried out showed that thecrystalline tiotropium bromide monohydrate obtainable by the aboveprocess has a simple monoclinic cell with the following dimensions:

-   a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.691°, V=2096.96 Å³.

These data were obtained using an AFC7R 4-circuit diffractometer(Rigaku) using monochromatic copper K_(α) radiation. The structuralresolution and refinement of the crystal structure were obtained bydirect methods (SHELXS86 Program) and FMLQ-refinement (TeXsan Program).

To prepare the suspensions according to the invention the crystallinetiotropium bromide monohydrate obtainable by the above process ismicronised by methods known per se in the art, to prepare the activesubstance in the form of the average particle size which corresponds tothe specifications according to the invention.

A method of determining the average particle size of the activesubstance will now be described.

Determining the Particle Size of Micronised Tiotropium BromideMonohydrate:

Measuring Equipment and Settings:

The equipment is operated according to the manufacturer's instructions.Measuring equipment: HELOS Laser diffraction spectrometer, SympaTecDispersing unit: RODOS dry disperser with suction funnel, SympaTecSample quantity: 50 mg-400 mg Product feed: Vibri Vibrating channel,Messrs. Sympatec Frequency of vibrating 40 rising to 100% channel:Duration of sample feed: 15 to 25 sec. (in the case of 200 mg) Focallength: 100 mm (measuring range: 0.9-175 μm) Measuring time: about 15 s(in the case of 200 mg) Cycle time: 20 ms Start/stop at: 1% on channel28 Dispersing gas: compressed air Pressure: 3 bar Vacuum: maximumEvaluation method: HRLDSample Preparation Product Feed:

About 200 mg of the test substance are weighed onto a piece of card.Using another piece of card all the larger lumps are broken up. Thepowder is then sprinkled finely over the front half of the vibratingchannel (starting about 1 cm from the front edge). After the start ofthe measurement the frequency of the vibrating channel is varied fromabout 40% up to 100% (towards the end of the measurement). The sampleshould be fed in as continuously as possible. However, the quantity ofproduct should not be too great, so as to ensure adequate dispersal.

The time taken to feed in the entire 200 mg sample is about 15 to 25sec., for example.

EXAMPLES OF FORMULATIONS

Suspensions containing other ingredients in addition to active substanceand propellant gas: a) 0.02% Tiotropium* 0.20% Polysorbate 20 99.78% HFA 227 b) 0.02% Tiotropium* 1.00% Isopropylmyristate 98.98%  HFA 227 c)0.02% Tiotropium*  0.3% Myvacet 9-45 99.68%  HFA 227 d) 0.04%Tiotropium* 1.00% Myvacet 9-08 98.96%  HFA 227 e) 0.04% Tiotropium*0.04% Polysorbate 80 99.92%  HFA 227 f) 0.04% Tiotropium* 0.005%  Oleicacid 99.955%  HFA 227 g) 0.02% Tiotropium*  0.1% Myvacet 9-45 60.00% HFA 227 39.88%  HFA 134a h) 0.02% Tiotropium* 0.30% Isopropylmyristate20.00%  HFA 227 79.68%  HFA 134a i) 0.02% Tiotropium* 0.01% Oleic acid60.00%  HFA 227 39.97%  HFA 134a*used in the form of the tiotropium bromide monohydrate (conversionfactor 1.2495)

Suspensions containing only active substance and propellant gas: j)0.02% Tiotropium* 99.98% HFA 227 k) 0.02% Tiotropium* 99.98% HFA 134a l)0.04% Tiotropium* 99.96% HFA 227 m) 0.04% Tiotropium* 99.96% HFA 134a n)0.02% Tiotropium* 20.00% HFA 227 79.98% HFA 134a o) 0.02% Tiotropium*60.00% HFA 227 39.98% HFA 134a p) 0.04% Tiotropium* 40.00% HFA 22759.96% HFA 134a q) 0.04% Tiotropium* 80.00% HFA 227 19.96% HFA 134a*used in the form of the tiotropium bromide monohydrate (conversionfactor 1.2495)

1-7. (canceled)
 8. A method of treating a disease, said disease beingchosen from those in which an anticholinergic confers a therapeuticbenefit, said method comprising administering by inhalation or nasalroute to a patient in need thereof a therapeutically effect amount of asuspension of crystalline tiotropium bromide monohydrate in propellantgases HFA 227 and/or HFA 134a, optionally in admixture with one or moreother propellant gases chosen from propane butane pentane,dimethylether, CHClF₂, CH₂F₂, CF₃CH₃, isobutane, isopentane andneopentane.
 9. A method of treating a respiratory complaints disease,said method comprising administering to a patient in need thereof atherapeutically effect amount of a suspension of crystalline tiotropiumbromide monohydrate in propellant gases HFA 227 and/or HFA 134a,optionally in admixture with one or more other propellant gases chosenfrom propane butane pentane, dimethylether, CHClF₂, CH₂F₂, CF₃CH₃,isobutane, isopentane and neopentane.
 10. The method according to claim9, wherein the diseases are chosen from asthma and COPD.